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MyVisionTest News Archive

Aug 28, 2010

C-reactive protein, CFH, and ARMS2/HTRA1 are independently associated with AMD riskHigh-sensitivity C-reactive protein (CRP) and polymorphisms in the CFH and ARMS2/HTRA1 genes are independently associated with risk of AMD, according to a new research study. Higher CRP level tends to confer a higher risk of age-related macular degeneration (AMD) within most genotype groups.

Studies have documented the importance of genetic, biologic, and environmental factors in the development of age-related macular degeneration (AMD). Genetic variants in the complement pathway, as well as the ARMS2/HTRA1 gene region, have been confirmed to be strongly associated with prevalence and incidence of AMD.

Given the hypotheses that inflammation plays a role in the pathogenesis of AMD and that cardiovascular risk factors are also related to AMD, including high-sensitivity C-reactive protein (CRP), a biomarker for systemic inflammation, we have evaluated the relationship between CRP and AMD. C-Reactive protein has been found to be associated with onset, as well as progression of AMD.

In this study, we have evaluated the joint and independent effects of serum CRP and 2 common single nucleotide polymorphisms, as well as their interactions on risk of intermediate and advanced stages of AMD.

The researchers defined AMD as large drusen, geographic atrophy, or neovascular disease.

Higher CRP levels were associated with a higher risk of AMD, controlling for genotype and demographic and behavioral risk factors, with odds ratio 2.6 for levels of 3.0 mg/L and above versus below 1.0 mg/L (95% confidence interval, 1.01-6.7). Single nucleotide polymorphisms (SNPs) in both genes were also independently associated with risk of AMD, controlling for the level of CRP and other factors. Presence of both highest level of CRP together with risk genotypes for both SNPs, conferred the highest risk of AMD (OR 5.4, 95% CI 1.4-21.1).

Discussion and Conclusions

This study's major findings are the apparent independent associations between CRP and AMD while controlling for genotype, and the higher risk of AMD within genetically susceptible individuals when CRP was in the higher range.

These results imply that both a biologic serum marker of inflammation as well as genetic factors in the inflammatory pathway (CFH) and another pathway (ARMS2/HTRA1) are related to AMD.

It is becoming increasingly apparent that inflammatory factors are associated with AMD, as shown by the relationship between AMD and genes in the complement pathways, as well as with inflammatory serum or plasma biomarkers.

The other known risk factors for AMD - namely, smoking and higher overall and abdominal obesity - are also directly related to higher levels of these inflammatory cytokines. These factors also increase oxidative stress, and antioxidant mechanisms are known to be related to AMD as shown by the lower risk of development of AMD and progression to advanced disease and visual loss with foods and supplements containing antioxidant vitamins and minerals and greater intake of omega-3 fatty acids.

The current study expands these findings and suggest that a genetic locus involved in the immune, inflammatory pathway, as well as a genetic locus with as of yet unclear function (ARMS2/HTRA1), together with a systemic marker of inflammation, CRP, act independently to increase risk of AMD, adjusting for smoking, BMI, and antioxidants. The combined effects of genetic susceptibility and higher levels of the inflammatory marker increase risk above the individual risks attributed to each factor alone.

In conclusion, these results suggest that high sensitivity CRP and the CFHY402H and ARMS2/HTRA1 genetic variants are independently related to risk of AMD. Although genetic factors confer a strong predisposition, environmental and biologic factors such as smoking and BMI, and factors leading to higher levels of the systemic inflammatory marker, CRP, can modify genetic susceptibility to AMD.

WHAT IT MEANS TO YOU: CRP is a nonspecific marker of systemic inflammation. In other words, anything that increases inflammation in the body will tend to increase CRP levels. There is a growing body of evidence indicating the CRP is an important marker of AMD risk. This study clearly demonstrates that CRP is related to AMD risk independent of genotype. While the precise role of inflammation in the development of AMD remains to be defined, it appears that those factors that raise CRP (such as smoking and obesity) also increase AMD risk.